Hepatitis B virus (HBV) is a kind of DNA virus that causes human acute or chronic hepatitis. As HBV infection is a direct cause of serious liver disease including cirrhosis and hepatocellular carcinoma in humans, hepatitis B is a major threat to human health. HBV-DNA (deoxyribonucleic acid) is the core of HBV and the basis of viral replication. Nucleotides can inhibit viral polymerases by competitive binding to the natural deoxyribose substrate directly, and terminate the DNA chain by inserting DNA. Thus, nucleotides, such as Cidofovir, Adefovir, Lamivudine, and Tenofovir, are the main drugs for treating hepatitis B. Tenofovir is a novel nucleotide reverse transcriptase inhibitor, which is effective against a variety of viruses for the treatment of viral infections. As the phosphate group is a dianion at physiological pH, tenofovir has poor cell membrane permeability, low bioavailability, and dose-dependent renal toxicity, which limits its therapeutic effect. Thus, tenofovir must be prepared into a phosphonate prodrug form via various technical means, such as esterification and salification, for clinical applications. For example, Tenofovir disoproxil fumarate developed by Gilead Sciences Inc. is the first generation oral active tenofovir prodrug for the treatment of HIV infection and hepatitis B.

As Tenofovir disoproxil fumarate is highly sensitive to serum enzyme mediated hydrolysis reactions, its drug concentration cannot be effectively increased at the active site. Moreover, two equivalents of potentially toxic formaldehyde are released upon metabolism, and side effects such as lactic acidosis, severe hepatomegaly and lipodystrophy have been found during clinical use. In order to improve the stability of tenofovir prodrug in plasma and reduce the metabolite-tenofovir concentration to reduce drug toxicity, many pharmaceutical companies are conducting research and development on the next generation of tenofovir prodrugs, and have made some progress. Some new prodrugs have been in phase I/II clinical studies. For example, International Patent Application WO0208241 discloses a kind of natural amino acid (monosubstituted) synthesized tenofovir phosphonamidate prodrug (e.g., GS-7340), and International Patent Application WO2009105513 discloses a kind of novel tenofovir phosphate bisamide prodrug. Compared to tenofovir phosphodiester, these novel prodrugs have improved plasma stability, thereby increasing the cumulative concentration of the active metabolite-tenofovir in peripheral blood mononuclear cells (PBMCs) and the therapeutic effect. For example, the total concentration of the active ingredient produced by GS-7340 in PBMCs is 10 times greater than tenofovir disoproxil, and 30 times greater than tenofovir. However, GS-7340 has certain degradation in plasma and 1-2% of the metabolite-tenofovir can be detected in plasma. So it is inevitable that GS-7340 has toxicity as a side effect generated by tenofovir disoproxil, which results in drug safety problems. Thus, it is important to further develop a tenofovir prodrug with high efficacy and low toxicity. With the purpose of further improving the stability of tenofovir disoproxil in plasma, the present invention synthesizes a series of tenofovir phosphonamidate prodrugs with disubstituted amino acids. This kind of prodrug is proven to be very stable in plasma and no metabolite-tenofovir is found in plasma. On the other hand, the concentration of active metabolite-tenofovir in PBMCs is increased significantly compared with GS-7340. Thus, the present invention makes it possible to provide a new generation of tenofovir prodrugs with high efficacy and low toxicity.